EP1680411A2 - Modulateurs des transporteurs des cassettes de fixation de l'atp contenant des groupes cycloalkyle ou pyranyle - Google Patents

Modulateurs des transporteurs des cassettes de fixation de l'atp contenant des groupes cycloalkyle ou pyranyle

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Publication number
EP1680411A2
EP1680411A2 EP04794652A EP04794652A EP1680411A2 EP 1680411 A2 EP1680411 A2 EP 1680411A2 EP 04794652 A EP04794652 A EP 04794652A EP 04794652 A EP04794652 A EP 04794652A EP 1680411 A2 EP1680411 A2 EP 1680411A2
Authority
EP
European Patent Office
Prior art keywords
compound
ring
aliphatic
phenyl
disease
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04794652A
Other languages
German (de)
English (en)
Inventor
Sara S. Hadida Ruah
Ashvani K. Singh
Mark T. Miller
Matthew Hamilton
Peter D.J. Grootenhuis
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Vertex Pharmaceuticals Inc
Original Assignee
Vertex Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Vertex Pharmaceuticals Inc filed Critical Vertex Pharmaceuticals Inc
Publication of EP1680411A2 publication Critical patent/EP1680411A2/fr
Withdrawn legal-status Critical Current

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    • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
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    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • the present invention relates to modulators of ATP- Binding Cassette (“ABC”) transporters or fragments thereof, including CF Transmembrane Regulator (“CFTR”), compositions thereof, and methods therewith.
  • the present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.
  • ABC transporters are a group of membrane transporter proteins that play a major role in the transport and protection of cells against a wide variety of pharmacological agents, potentially toxic drugs, and xenobiotics.
  • ABC transporters are homologous membrane proteins that bind and use cellular adenosine triphosphate (ATP) for their specific activities.
  • Some of these transporters were discovered as multidrug resistance proteins (like the MDR1-P glycoprotein, or the multidrug resistance protein, MRP1) , defending malignant cancer cells against chemotherapeutic agents.
  • MRP1-P glycoprotein or the multidrug resistance protein, MRP1
  • defending malignant cancer cells against chemotherapeutic agents Up until the present time, 48 Human ABC Transporters have been identified, and these have been arranged into 7 families based on their sequence identity and function.
  • ABC transporters play a variety of important physiological roles within the body, as well as providing a defense against harmful compounds from the environment . Moreover they represent important potential drug targets both in their own right, as well as, because in many cases therapeutic drugs are also transported out of the target cell by these molecules.
  • One of the members of the ABC transporter family namely, CFTR, is believed be the chloride channel responsible for cAMP-mediated chloride secretion in epithelial cells, and to play a key role in the secretion of chloride and maintenance of normal electrolyte transport throughout the body.
  • CFTR is a protein of approximately 1480 amino acids made up of two repeated elements, each comprising six transmembrane segments and a nucleotide-binding domain.
  • CFTR cystic fibrosis
  • the other elements include the epithelial Na + channel, ENaC, Na + /2C1 " /K + co-transporter, Na + -K + -ATPase pump and the basolateral membrane K + channels, that are responsible for the uptake of chloride into the cell. [0010] These elements work together to achieve directional transport across the epithelium via their selective expression and localization within the cell. Chloride absorption takes place by the coordinated activity of: (i) ENaC and CFTR present on the apical membrane; and (ii) the Na + -K + -ATPase pump and Cl- channels expressed on the basolateral surface of the cell.
  • COPD chronic obstructive pulmonary disease
  • COPD dry eye disease
  • Sj ⁇ gren's Syndrome Sj ⁇ gren's Syndrome.
  • COPD chronic obstructive pulmonary disease
  • Activators of mutant or wild-type CFTR offer a potential treatment of mucus hypersecretion and impaired mucociliary clearance that is common in COPD.
  • CFTR dry eye disease
  • CF and Sj ⁇ grens's syndrome Increasing anion secretion via CFTR would enhance fluid transport from the corneal endothelial cells and secretory glands surrounding the eye to increase corneal hydration.
  • Sj ⁇ grens's syndrome is an autoimmune disease in which the immune system attacks moisture-producing glands throughout the body, including the eye, mouth, skin, respiratory tissue, liver, vagina, and gut. Symptoms include dry eye, mouth, and vagina, as well as lung disease. The disease is also associated with rheumatoid arthritis, systemic lupus, systemic sclerosis, and polymypositis/dermatomyositis . Defective protein trafficking is believed to cause the disease for which treatment options are limited. Modulators of CFTR activity may hydrate the various organs afflicted by the disease and help to elevate the associated symptoms.
  • the diseases associated with the first class of ER malfunction are CF (due to misfolded ⁇ F508-CFTR) , hereditary emphysema (due to ⁇ l-antitrypsin; non Piz variants) , hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I- cell disease/pseudo-Hurler, mucopolysaccharidoses (due to lysosomal processing enzymes) , Sandhof/Tay-Sachs (due to ⁇ - hexosaminidase) , Crigler-Naj jar type II (due to UDP
  • the diseases associated with the latter class of ER malfunction are glycanosis CDG type 1, hereditary emphysema (due to ⁇ l- antitrypsin (PiZ variant) , congenital hyperthyroidism, osteogenesis imperfecta (due to Type I, II, IV procollagen) , hereditary hypofibrinogenemia (due to fibrinogen) , ACT deficiency (due to c.l-antichymotrypsin) , Diabetes insipidus (Dl) , neurophyseal Dl (due to Vasopressin hormone/V2- receptor) , neprogenic Dl (due to aquaporin II) , Charcot-Marie Tooth syndrome (due to Peripheral myelin protein 22) , Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease (due to APP and presenilins) , Parkinson's disease, amyotroph
  • Diarrhea in barn animals and pets such as cows, pigs and horses, sheep, goats, cats and dogs, also known as scours, is a major cause of death in these animals. Diarrhea can result from any major transition, such as weaning or physical movement, as well as in response to a variety of bacterial or viral infections and generally occurs within the first few hours of the animal's life.
  • the most common diarrheal causing bacteria is enterotoxogenic E-coli (ETEC) having the K99 pilus antigen.
  • ETEC enterotoxogenic E-coli
  • Common viral causes of diarrhea include rotavirus and coronavirus.
  • Other infectious agents include cryptosporidium, giardia lamblia, and salmonella, among others.
  • Symptoms of rotaviral infection include excretion of watery feces, dehydration and weakness. Coronavirus causes a more severe illness in the newborn animals, and has a higher mortality rate than rotaviral infection. Often, however, a young animal may be infected with more than one virus or with a combination of viral and bacterial microorganisms at one time. This dramatically increases the severity of the disease. [0022] Accordingly, there is a need for modulators of an ABC transporter activity, and compositions thereof, that can be used to modulate the activity of the ABC transporter in the cell membrane of a mammal . [0023] There is a need for methods of treating ABC transporter mediated diseases using such modulators of ABC transporter activity.
  • ABC-transporter as used herein means an ABC-transporter protein or a fragment thereof comprising at least one binding domain, wherein said protein or fragment thereof is present in vivo or in vi tro.
  • binding domain as used herein means a domain on the ABC-transporter that can bind to a modulator. See, e.g., Hwang, T. C. et al . , J . Gen. Physiol. (1998): 111(3), 477-90.
  • CFTR cystic fibrosis transmembrane conductance regulator or a mutation thereof capable of regulator activity in part or full, including, but not limited to, ⁇ F508 CFTR and G551D CFTR (see, e.g., http://www.genet.sickkids.on.ca/cftr/, for CFTR mutations) .
  • COPD chronic obstructive pulmonary disease and comprises chronic obstructive bronchitis, and emphysema.
  • modulating as used herein means increasing or decreasing by a measurable amount.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein.
  • a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
  • aliphatic or "aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic, bicyclic, or tricyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle” "cycloaliphatic” or “cycloalkyl” ) , that has a single point of attachment to the rest of the molecule.
  • aliphatic groups contain 1-20 aliphatic carbon atoms, i.e., ( (C1-C20) alkyl) . In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms, i.e., ( (C1-C10) alkyl) . In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms, i.e., ( (C1-C8) alkyl .
  • aliphatic groups contain 1-6 aliphatic carbon atoms, i.e., ( (C1-C6) alkyl, and in yet other embodiments aliphatic groups contain 1-4 aliphatic carbon atoms, i.e., ( (C1-C4) alkyl .
  • cycloaliphatic refers to a monocyclic C3-C8 hydrocarbon or bicyclic or tricyclic C8-C12 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule wherein any individual ring in said bicyclic ring system has 3-7 members.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl) alkyl, (cycloalkenyl) alkyl or (cycloalkyl) alkenyl .
  • heteroaliphatic means aliphatic groups wherein one or two carbon atoms are independently replaced by one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon.
  • Heteroaliphatic groups may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and include “heterocycle” , “heterocyclyl” , “heterocycloaliphatic” , or “heterocyclic” groups. [0039] The term “heterocycle”, “heterocyclyl”,
  • heterocycloaliphatic or “heterocyclic” as used herein means non-aromatic, monocyclic, bicyclic, or tricyclic ring systems in which one or more ring members is an independently selected heteroatom.
  • the "heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or “heterocyclic” group has three to fourteen ring members in which one or more ring members is a heteroatom independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the system contains 3 to 7 ring members .
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4- dihydro-2H-pyrrolyl) , NH (as in pyrrolidinyl) or NR + (as in N- substituted pyrrolidinyl)).
  • alkoxy or “thioalkyl” , as used herein, refers to an alkyl group, as previously defined, attached to the principal carbon chain through an oxygen (“alkoxy”) or sulfur ( “thioalkyl” ) atom.
  • haloalkyl means alkyl, alkenyl or alkoxy, as the case may be, substituted with one or more halogen atoms.
  • halogen means F, Cl, Br, or I.
  • aryl used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • aryl may be used interchangeably with the term “aryl ring” .
  • aryl also refers to heteroaryl ring systems as defined hereinbelow.
  • heteroaryl used alone or as part of a larger moiety as in “heteroaralkyl” or “heteroarylalkoxy” , refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members ' , wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains 3 to 7 ring members.
  • heteroaryl may be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic” .
  • An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more substituents.
  • Optional substituents on the aliphatic group of R° are selected from NH 2 , NH (Cx ⁇ aliphatic) , N(C ⁇ - 4 aliphatic) 2 , halogen, C ⁇ _ 4 aliphatic, OH, 0 (C ⁇ -4 aliphatic) , N0 2 , CN, C0 2 H, C0 2 (C 1 . 4 aliphatic) , 0(haloC ⁇ - 4 aliphatic), or haloCi- aliphatic, wherein each of the foregoing C ⁇ _aliphatic groups of R° is unsubstituted.
  • Optional substituents on the aliphatic group of R * are selected from NH 2 , NH(C 1-4 aliphatic), N(C1-C4 aliphatic) 2 , halogen, (C1-C4) aliphatic, OH, 0( (C1-C4) aliphatic) , N0 2 , CN, C0 2 H, C0 2 ( (C1-C4) aliphatic) , 0 (halo (C1-C4) aliphatic) , or halo ( (C1-C4) aliphatic) , wherein each of the foregoing (C1-C4) aliphatic groups of R * is unsubstituted .
  • Optional substituents on the aliphatic group or the phenyl ring of R + are selected from NH 2 , NH ( (C1-C4) aliphatic) , N( (C1-C4) aliphatic) 2 , halogen, (C1-C4) aliphatic, OH, 0( (C1-C4) aliphatic) , N0 2 , CN, C0 2 H, C0 2 ( (C1-C4) aliphatic) , O (halo (C1-C4) aliphatic) , or halo ( (C1-C4) aliphatic) , wherein each of the foregoing Cx ⁇ aliphatic groups of R + is unsubstituted.
  • alkylidene chain refers to a straight or branched carbon chain that may be fully saturated or have one or more units of unsaturation and has two points of attachment to the rest of the molecule.
  • R° or R + , or any other variable similarly defined herein
  • two independent occurrences of R° are taken together with the atom(s) to which each variable is bound to form a 3-8-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Exemplary rings that are formed when two independent occurrences of R° (or R + , or any other variable similarly defined herein) are taken together with the atom(s) to which each variable is bound include, but are not limited to the following: a) two independent occurrences of R° (or R + , or any other variable similarly defined herein) that are bound to the same atom and are taken together with that atom to form a ring, for example, N(R°) 2/ where both occurrences of R° are taken together with the nitrogen atom to form a piperidin-1- yl , piperazin-1-yl , or morpholin-4-yl group; and b) two independent occurrences of R° (or R + , or any other variable similarly defined herein) that are bound to different atoms and are taken together with both of those atoms to form a ring, for example where a phenyl group is substituted with two
  • the present invention relates to compounds of formula I:
  • A is C(O) , or S0 2 ;
  • R c and R D are independently selected from H, (C1-C4) alkyl , and aryl, or may be taken together to form a (C3-C8) cycloalkyl or heterocyclic;
  • R E is H, (C1-C4) alkyl optionally substituted with a substituent selected from CN, N0 2 , CF 3 , 0CF 3 , OH, SR 6 , S(0)R 6 , S0 R 6 , COOH, COOR 6 , OR 6 or phenyl optionally substituted with
  • R' B is aryl or heterocyclic
  • L is (Cl-C6)alkylidene, -O- ( (C1-C6) alkylidene) , ( (Cl-6) alkylidene) -0- , or a bond, wherein up to two carbon atoms in said alkylidene in L are independently replaced with O, S, or N;
  • W is aryl, heterocyclic, or (C5-C7) cycloalkyl ;
  • m and n are independently 0 to 5;
  • R B and R z are independently selected from R 1 , R 2 , R 3 , R 4 , or R5, wherein: R 1 is oxo, R 6 or ( (C1-C4) aliphatic) n -Y; n is 0 or 1 ;
  • Y is halo, CN, N0 2 , CF 3 , OCF3 , OH, SR 6 , S(0)R 6 , S0 2 R 6 , NH 2 , NHR 6
  • R 5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R 1 substituents
  • R 6 is H or aliphatic, wherein R 6 optionally comprises a R 7 substituent
  • R 7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R 7 optionally comprises up to 2 substituents independently chosen from H, (C]_-Cg) -straight or branched alkyl, (C 2 -Cg) straight or branched alkenyl or alkynyl, 1 , 2-methylenedioxy, 1 , 2 -ethylenedioxy, or (CH2) n ⁇ Q;
  • Q is selected from halo, CN, N0 2 , CF3 , OCF3 , OH, S-aliphatic, S (O)
  • amino protecting group refers to a suitable chemical group that may be attached to a nitrogen atom.
  • protecting refers to when the designated amino group is attached to a suitable chemical group (e.g., capping group). Examples of suitable amino capping groups are described in T.W. Greene et al . , Protective Groups in Organic Synthesis, 3d. Ed. , John Wiley and Sons (1999) ; L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994) ; L. Paquette, ed. Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and are exemplified in certain of the specific compounds used in this invention.
  • the present invention provides a compound of formula II :
  • A is C(0) or S0 2 ;
  • R c and R D taken together form a 3-6 membered cycloalkyl ring or 4-pyranyl ring;
  • R E is H, (C1-C4) alkyl optionally substituted with a substituent selected from (C1-C4) alkyl selected CN, N0 2 , CF3 , OCF3, OH, SR 6 , S(0)R 6 , S0 2 R 6 , COOH, COOR 6 , OR 6 or phenyl optionally substituted with R z ;
  • B is phenyl;
  • L is a bond
  • W is a 5-14 membered monocyclic, bicyclic, or tricyclic heterocyclic or heteroaryl ring
  • m and n are independently 0 to 5
  • Z is diphenylmethyl wherein each phenyl has up to 5 R z is substituents
  • R B and R z are independently selected from R 1 , R 2 , R 3 , R 4 , or R 5 , wherein: R 1 is oxo, R 6 or ( (C1-C4) aliphatic) n -Y; n is 0 or 1; Y is halo, CN, N0 2 , CF 3 , OCF 3 , OH, SR 6 , S(0)R 6 , S0 2 R 6 , NH 2 , NHR 6 , N(R 6 ) 2 , NR 6 R 8 , COOH, COOR 6 or OR 6 ; or two R 1 on adjacent ring atoms, taken together, form 1 , 2
  • R E when R and R taken together form a cyclopentyl ring, R E is hydrogen, A is C(O), and ring W together with R z and m is diphenylmethyl, then ring B together with (R B ) n is not phenyl, 4-ethoxyphenyl, 4-butoxyphenyl, 4-isobutoxyphenyl, or 4 -methoxyphenyl .
  • A is C(O) .
  • A is S0 2 .
  • R E is hydrogen.
  • R E is C1-C4 alkyl .
  • R c and R D taken together, form a 4-pyranyl ring.
  • R c and R D taken together, form a 3-6 membered cycloalkyl ring.
  • R c and R D taken together, form a 5-6 membered cycloalkyl ring.
  • R c and R D taken together, form a 5-membered cycloalkyl ring.
  • R c and R D taken together, form a 6-membered cycloalkyl ring.
  • W is an optionally substituted indolyl, benzofuranyl , or benzothienyl .
  • W is is indol-2- yl or indol-3-yl.
  • W is benzofuran-2 -yl .
  • W is benzothien-2-yl .
  • W is an optionally substituted pyrazolyl or indazolyl .
  • W is an optionally substituted pyrazol-3-yl or pyrazol-4-yl .
  • W is an optionally substituted indazol-3-yl .
  • W is an optionally substituted phenyl .
  • W is an optionally substiuted six-membered heteroaromatic ring having up to three heteroatoms selected from O, S, or N.
  • W is pyridyl .
  • Z is diphenylmethyl.
  • W is an optionally substituted ring selected from furanyl , thienyl , isoxazolyl, or pyrrolyl .
  • W is an optionally substituted 10-12 membered bicyclic, heteroaromatic ring.
  • W is an optionally substituted ring selected from quinolinyl or cinnolinyl.
  • R c and R D each is methyl.
  • R 8 is acetyl, arylsulfonyl or alkylsuifonyl .
  • Another embodiment of the present invention provides a method of treating an ABC transporter mediated disease in a mammal, comprising the step of administering to said mammal a composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof.
  • a preferred aspect of the present embodiment is where the ABC transporter mediated disease is selected from cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-cibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage- diseases, such as I-cell disease/Pseudo-Hurler, secretory diarrhea or polycystic kidney disease, mucopolysaccharidoses , Sandhof/Tay-Sachs, Crigler-Naj jar type II, polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, heredit
  • An especially preferred method is where the disease is CF.
  • Another embodiment of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising: a. a compound of the present invention; b. a pharmaceutically acceptable carrier; and c. an additional agent selected from a mucolytic agent, bronchodialator, an antibiotic, an anti-infective agent, an anti- inflammatory agent, CFTR modulator other than a compound of the present invention, or a nutritional agent.
  • Another embodiment of the present invention provides a method of modulating ABC transporter activity, comprising the step of contacting said ABC transporter with a compound of the present invention.
  • a preferred aspect of this embodiment is where the ABC transporter or a fragment thereof is in vivo. Another preferred aspect of this embodiment is where the ABC transporter or a fragment thereof is in vi tro .
  • the present invention provides a method of increasing the number of functional ABC transporters in a membrane of a cell, comprising the step of contacting said cell with a compound of formula (I) .
  • the term "functional ABC transporter" as used herein means an ABC transporter that is capable of transport activity.
  • said functional ABC transporter is CFTR.
  • Another embodiment of the present invention provides a kit for use in measuring the activity of a ABC transporter or a fragment thereof in a biological sample in vi tro or in vivo, comprising: a. a composition comprising a compound of the present invention; and b. instructions for: i) contacting said composition with the biological sample; and ii) measuring activity of said ABC transporter or fragment thereof .
  • a preferred aspect of this embodiment is where the ABC transporter is CFTR.
  • R c and R D are independently selected from H, C ⁇ _ 4 alkyl, and aryl, or may be taken together to form a (C3-C8) cycloalkyl; B is aryl; and Z is (C1-C6) alkyl , aryl, (Cl-C4alkyl)aryl, C5-C7cycloalkyl , or ( (Cl-4) alkyl) C 5 _ 7 cycloalkyl .
  • a preferred embodiment of the present invention is where A is C(O) , and L is a bond.
  • a preferred embodiment of the present invention is where R c and R D taken together form (C3-C8) cycloalkyl .
  • a particularly preferred embodiment of the present invention is where R c and R D taken together form cyclopentyl.
  • a preferred embodiment of the present invention is where R c and R D taken together form a heterocyclic. [0088] A particularly preferred embodiment of the present invention is where R c and R D taken together form pyranyl . In certain embodiments, R c and R D taken together form 4-pyranyl. [0089] Yet another particularly preferred embodiment of the present invention is where R c and R D are H. [0090] Yet another particularly preferred embodiment of the present invention is where R c and R D are methyl . [0091] A preferred embodiment of the present invention is where B is aryl.
  • a particularly preferred embodiment of the present invention is where B is phenyl .
  • a preferred embodiment of the present invention is where Z is aryl.
  • Another preferred embodiment of the present invention is where Z is pyridinyl .
  • Another preferred embodiment of the present invention is where Z is phenyl.
  • Another preferred embodiment of the present invention is where Z is benzofuran.
  • Another preferred embodiment of the present invention is where Z is benzothiophenyl .
  • Another preferred embodiment of the present invention is where Z is indolyl .
  • Another preferred embodiment of the present invention is where Z is pyrazolyl .
  • Another preferred embodiment of the present invention is where Z is furanyl .
  • Another preferred embodiment of the present invention is where Z is quinolinyl .
  • Another preferred embodiment of the present invention is where Z is isoquinolinyl .
  • Another preferred embodiment of the present invention is where Z is is cinnolinyl.
  • An especially preferred embodiment of the present invention is where Z is benzofuranyl , and R c and R D taken together form cyclohexyl .
  • Another especially preferred embodiment is where B is a substituted phenyl .
  • An especially preferred embodiment of the present invention is a compound where Z is benzofuranyl , R c and R D taken together form cyclohexyl, and B is a substituted phenyl as represented by formula II:
  • R z is independently selected from (C1-C4) alkyl, (C1-C4) alkoxy, and halo, particularly methyl, methoxy, F, or Cl; n is 0 to 4 ; R B is independently selected from halo, and (C1-C4) alkoxy; and m is 0 to 5.
  • the compounds of the present invention can be prepared by methods well known in the art.
  • An exemplary method of producing compounds of the present invention is shown below in Schemes 1-3.
  • Scheme 1 illustrates an exemplary method for producing amine intermediates for compounds of the present invention wherein R c and R D cyclize to form a ring: i) XCH 2 (CH 2 )n ' X, NaH, THF (X is C , Br, I; n' is 1 to 4) ii) LiAlH 4 , ether [00111] An optionally substituted (R*) 2-phenylacetonitrile is reacted with an appropriate dihalo-alkyl compound, sodium hydride or the like, in THF or a similar solvent. The resulting spiro compound is reacted with lithium aluminum hydride or similar reducing reagent to provide the desired cyclic amine. [00112] Scheme 2 below illustrates- an exemplary method for producing amine intermediates for the present invention wherein R c and R D do not cyclize to form a ring. [00113] Scheme 2:
  • Scheme 3 below illstrates an exemplary method for producing certain compounds of the present invention using the amine intermediates of, e.g., Scheme 1 and Scheme 2 above.
  • the ABC transporter mediated disease is selected from Cystic fibrosis, COPD, Asthma, chronic pancreatitis, pneumonia, polycystic kidney disease, Hereditary emphysema, Hereditary hemochromatosis, Coagulation-Fibrinolysis deficiencies, such as Protein C deficiency, Type 1 hereditary angioedema, Lipid processing deficiencies, such as Familial hypercholesterolemia, Type 1 chylomicronemia, Abetalipoproteinemia, Lysosomal storage diseases, such as I- cell disease/Pseudo-Hurler, Mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Naj jar type II,
  • Glycanosis CDG type 1 Hereditary emphysema, Congenital hyperthyroidism, Osteogenesis imperfecta, Hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (Dl) , Neurophyseal Dl , Neprogenic Dl , Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders such as Huntington, Spinocerebullar ataxia type I, Spinal and bulbar muscular atrophy, Dentatorubal pallidoluysian
  • the ABC transporter mediated disease is cystic fibrosis.
  • Another embodiment of the present invention provides a method of treating a disease selected from Cystic fibrosis, COPD, asthma, chronic pancreatitis, pneumonia, polycytic kidney disease, Hereditary emphysema, Hereditary hemochromatosis, Coagulation-Fibrinolysis deficiencies, such as Protein C deficiency, Type 1 hereditary angioedema, Lipid processing deficiencies, such as Familial hypercholesterolemia, Type 1 chylomicronemia, Abetalipoproteinemia, Lysosomal storage diseases, such as I- cell disease/Pseudo-Hurler, Mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Naj jar type II,
  • Polyendocrinopathy/Hyperinsulemia Diabetes mellitus, Laron dwarfism, Myleoperoxidase deficiency, Primary hypoparathyroidism, Melanoma, Glycanosis CDG type 1, Hereditary emphysema, Congenital hyperthyroidism, Osteogenesis imperfecta, Hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (Dl), Neurophyseal Dl , Neprogenic Dl , Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders asuch as Huntington, Spinocerebullar ataxia type I, Spinal and bulbar muscular atrophy, Dentatorubal pallidoluysian, and Myotonic dystrophy, as well as
  • the disease so treated is selected from Tangier's disease, stargardt disease 1, age related macular dystrophy 2, retinintis pigmentosa, bare lymphocyte syndrome, PFIC-3, anemia, progressive intrahepatic cholestasis-2, Dublin-Johnson syndrome, Pseudoxanthoma elasticum, cystic fibrosis, familial persistent hyperinsulinemic hyproglycemia of infancy, adrenolecukodystrophy, sitosterolemia, chronic obstructive pulmonary disease, asthma, disseminated bronchiectasis, chronic pancreatitis, male infertility, emphysema, or pneumonia .
  • the ABC transporter mediated disease is secretory diarrhea, COPD, or polycystic kidney disease in a mammal.
  • the present invention provides a method of treating cystic fibrosis or secretory diahrrea comprising the step of administering to said mammal a composition comprising the step of administering to said mammal a composition comprising a compound of the present invention, or a preferred embodiment thereof as set forth above. Most preferably, said disease is cystic fibrosis.
  • the present invention provides a method of modulating CFTR activity in a cell membrane ("potentiating") of a mammal in need thereof, comprising the step of administering to said mammal a composition comprising a compound of the present invention as defined above.
  • the preferred embodiments of the compounds of the present invention useful in potentiating the activity of CFTR include the preferred embodiments of the present invention described above.
  • the present invention provides a method of increasing the number of functional ABC transporters in a membrane of a cell, comprising the step of contacting said cell with a compound of the present invention.
  • the term "functional ABC transporter" as used herein means an ABC transporter that is capable of transport activity.
  • said functional ABC transporter is CFTR.
  • the preferred embodiments of compounds of the present invention useful in increasing the number of functional ABC transporters include preferred embodiments of compounsd of the present invention as described above.
  • the present invention provides a method of modulating activity of an anion channel in vi tro or in vivo, comprising the step of contacting said channel with a compound of the present invention.
  • said anion channel is a chloride channel or a bicarbonate channel. More preferably, said anion channel is a chloride channel .
  • the present invention provides a method of treating an anion channel mediated disease in a mammal, comprising the step of administering to said mammal a composition comprising a compound according to the present invention.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising: (i) a compound of the present invention as described above ; (ii) a pharmaceutically acceptable carrier; and (iii) an additional agent selected from a mucolytic agent, bronchodialator, an anti-biotic, an anti-infective agent, an anti-inflammatory agent, CFTR modulator other than a compound of the present invention, or a nutritional agent.
  • Preferred embodiments of compounds the present invention in the above pharmaceutical composition are those as described above.
  • the present invention provides a kit for use in measuring the activity of a ABC transporter or a fragment thereof in a biological sample in vi tro or in vivo, comprising: (i) a composition comprising a compound of the present invention; and (ii) instructions for: a) contacting the composition with the biological sample; b) measuring activity of said ABC transporter or a fragment thereof .
  • the kit is useful in measuring the activity of CFTR.
  • the compounds of this invention may be prepared in general by methods known to those skilled in the art for analogous compounds, as illustrated by the general schemes below, and the preparative examples that follow.
  • Starting materials are commercially available from typical chemical reagent supply companies, such as, Aldrich Chemicals Co., Sigma Chemical Company, ChemBridge Corporation, and the like.
  • structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • the present invention provides compounds that are useful as modulators of ABC transporters and thus are useful in treating a disease selected from Cystic fibrosis, COPD, chronic pancreatitis, pneumonia, polycystic kidney disease, Hereditary emphysema, Hereditary hemochromatosis, Coagulation-Fibrinolysis deficiencies, such as Protein C deficiency, Type 1 hereditary angioedema, Lipid processing deficiencies, such as Familial hypercholesterolemia, Type 1 chylomicronemia, Abetalipoproteinemia, Lysosomal storage diseases, such as I- cell disease/Pseudo-Hurler, Mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Naj jar type II,
  • Polyendocrinopathy/Hyperinsulemia Diabetes mellitus, Laron dwarfism, Myleoperoxidase deficiency, Primary hypoparathyroidism, Melanoma, Glycanosis CDG type 1, Hereditary emphysema, Congenital hyperthyroidism, Osteogenesis imperfecta, Hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (Dl) , Neurophyseal Dl, Neprogenic Dl , Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders asuch as Huntington, Spinocerebullar ataxia type I, Spinal and bulbar muscular atrophy, Dentatorubal pallidoluysian, and Myotonic dystrophy, as well
  • compositions comprising any of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle.
  • these compositions optionally further comprise one or more additional therapeutic agents.
  • certain of the compounds of present invention can exist in free' form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof.
  • a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof .
  • pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • a “pharmaceutically acceptable salt” means any non-toxic salt or salt of an ester of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof.
  • compositions of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, ⁇ maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, ⁇ maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1- 4alkyl)4 salts.
  • This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersable products may be obtained by such quaternization.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein; includes any and all solvents, ' diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof.
  • any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component (s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention.
  • materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc
  • the present invention provides a method of treating a condition, disease, or disorder implicated by ABC transporter activity.
  • the present invention provides a method of treating a condition, disease, or disorder implicated by a deficiency of ABC transporter activity, the method comprising administering a composition comprising a compound of Formula I to a subject, preferably a mammal, in need thereof.
  • the present invention provides a method of treating cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation- cibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I- cell disease/pseudo-Hurler, secretory diarrhea or polycystic kidney disease, mucopolysaccharidoses , Sandhof/Tay-Sachs , Crigler-Naj jar type II, polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, hereditary e
  • the present invention provides a method of treating cystic fibrosis comprising the step of administering to said mammal a composition comprising the step of administering to said mammal an effective amount of a composition comprising a compound of the present invention.
  • an "effective amount" of the compound or pharmaceutically acceptable composition is that amount effective for treating or lessening the severity of one or more of cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-cibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I- cell disease/pseudo-Hurler, secretory diarrhea or polycystic kidney disease, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Naj jar type II, polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma,
  • the compounds and compositions, according to the method of the present invention may be administered using any amount and any route of administration effective for treating or lessening the severity of one or more of cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation- cibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I- cell disease/pseudo-Hurler, secretory diarrhea or polycystic kidney disease, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Naj jar type II, polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism
  • the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like.
  • the compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
  • dosage unit form refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.
  • patient means an animal, preferably a mammal, and most preferably a human.
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops) , bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated.
  • the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents,
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3- butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides .
  • fatty acids such as oleic acid are used in the preparation of injectables .
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle.
  • injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides) . Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues .
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound .
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol
  • the dosage form may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient (s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions examples include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • the active compounds can also be in microencapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may-- also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient (s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention.
  • the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms are prepared by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel .
  • the compounds of the invention are useful as modulators of ABC transporters.
  • the compounds and compositions are particularly useful for treating or lessening the severity of a disease, condition, or disorder where hyperactivity or inactivity of ABC transporters is implicated in the disease, condition, or disorder.
  • hyperactivity or inactivity of an ABC transporter is implicated in a particular disease, condition, or disorder
  • the disease, condition, or disorder may also be referred to as a "ABC transporter-mediated disease, condition or disorder”.
  • the present invention provides a method for treating or lessening the severity of a disease, condition, or disorder where hyperactivity or inactivity of an ABC transporter is implicated in the disease state.
  • the activity of a compound utilized in this invention as a modulator of an ABC transporter may be assayed according to methods described generally in the art and in the Examples herein.
  • the compounds and pharmaceutically acceptable compositions of the present invention can be employed in combination therapies, that is, the compounds and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures.
  • the particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder) , or they may achieve different effects (e.g., control of any adverse effects).
  • additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition are known as "appropriate for the disease, or condition, being treated” .
  • the amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
  • the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent .
  • the compounds of this invention or pharmaceutically acceptable compositions thereof may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters.
  • the present invention in another aspect, includes a composition for coating an implantable device comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device.
  • the present invention includes an implantable device coated with a composition comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a - I l l
  • coatings and the general preparation of coated implantable devices are described in US Patents 6,099,562; 5,886,026; and 5,304,121.
  • the coatings are typically biocompatible polymeric materials such as a hydrogel polymer, poly ethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof.
  • the coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccarides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.
  • Another aspect of the invention relates to modulating ABC transporter activity in a biological sample or a patient (e.g., in vitro or in vivo), which method comprises administering to the patient, or contacting said biological sample with a compound of the present invention or a composition comprising said compound.
  • biological sample includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
  • Modulation of ABC transporter activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art.
  • a method of modulating activity of an anion channel in vitro or in vivo comprising the step of contacting said channel with a compound of the present invention.
  • the anion channel is a chloride channel or a bicarbonate channel .
  • the anion channel is a chloride channel .
  • the present invention provides a method of increasing the number of functional ABC transporters in a membrane of a cell, comprising the step of contacting said cell with a compound of the present invention.
  • the term "functional ABC transporter” as used herein means an ABC transporter that is capable of transport activity.
  • said functional ABC transporter is CFTR.
  • the activity of the ABC transporter is measured by measuring the transmembrane voltage potential .
  • Means for measuring the voltage potential across a membrane in the biological sample may employ any of the known methods in the art, such as optical membrane potential assay or other electrophysiological methods .
  • the optical membrane potential assay utilizes voltage-sensitive FRET sensors described by Gonzalez and Tsien (See, Gonzalez, J. E. and R. Y.
  • These voltage sensitive assays are based on the change in fluorescence resonant energy transfer (FRET) between the membrane-soluble, voltage-sensitive dye, DiSBAC2(3), and a fluorescent phospholipid, CC2-DMPE, which is attached to the outer leaflet of the plasma membrane and acts as a FRET donor.
  • FRET fluorescence resonant energy transfer
  • CC2-DMPE fluorescent phospholipid
  • Changes in membrane potential (Vm) cause the negatively charged DiSBAC2(3) to redistribute across the plasma membrane and the amount of energy transfer from CC2-DMPE changes accordingly.
  • the changes in fluorescence emission can be monitored using VIPRTM II, which is an integrated liquid handler and fluorescent detector designed to conduct cell- based screens in 96- or 384-well microtiter plates.
  • the present invention provides a kit for use in measuring the activity of a ABC transporter or a fragment thereof in a biological sample in vitro or in vivo comprising (i) a composition comprising a compound of the present invention; and (ii) instructions for a) contacting the composition with the biological sample and b) measuring activity of said ABC transporter or a fragment thereof.
  • the kit further comprises instructions for a) contacting an additional composition with the biological sample; b) measuring the activity of said ABC transporter or a fragment thereof in the presence of said additional compound, and c) comparing the activity of the ABC transporter in the presence of the additional compound with the density of the ABC transporter in the presence of a composition of the present invention.
  • the kit is used to measure the density of CFTR.
  • the reaction mixture was cooled to room temperature and quenched with the slow addition of methanol.
  • the reaction mixture was evaporated to dryness and purified by column chromatography on silica gel to yield a pale yellow oil (3.65 g, 14.9 mmol, 52.8 %) .
  • the resulting 1- (3 , 4-dimethoxy- phenyl) -cyclohexanecarbonitrile (2.00 g, 8.15 mmol) was dissolved in dry ether (40 mL) and cooled to 0°C under an atmosphere of nitrogen. Lithium aluminum hydride (8.15 mL, IM in ether) was slowly added and the reaction mixture was allowed to warm to room temperature and stirred for 16 hours.
  • reaction mixture was cooled to 0°C and quenched with 0.34 mL water, 0.34 mL of 15 % sodium hydroxide, and then an additional 1.4 mL of water.
  • the reaction mixture was then filtered through celite, washed with water and a saturated aqueous sodium chloride solution. The filtrate was evaporated to dryness to give a colorless oil (1.91 g, 7.66 mmol, 94.0 %) .
  • ESI-MS m/z calc. 249.2, found 250.2 (M+l) + . Retention time of 1.76 minutes.
  • reaction mixture was evaporated to dryness and purified by column chromatography on silica gel using a gradient of 0-40 % ethyl acetate in hexanes. The pure fractions were combined and evaporated to dryness to yield a white solid (0.426 g, 1.09 mmol, 37.7 %) .
  • ESI-MS m/z calc. 390.2, found 391.2 (M+l) + . Retention time of 3.94 minutes. ⁇ .
  • Benzofuran-2 -carboxylic acid (1-benzo [1, 3] dioxol-5-yl- cyclopentylmethyl) -amide.
  • C- (1-Benzo [1,3] dioxol-5-yl -cyclopentyl) -methylamine (43.8 mg, 0.200 mmol)
  • benzofuran-2 -carbonyl chloride (36.1 mg, 0.200 mmol) were dissolved in 2 mL of 1,4-dioxane containing triethylamine (83.6 ⁇ L, 0.600 mmol).
  • Phenethylamine (72.7 mg, 0.600 mmol) and O- (7-azabenzotriazol-l-yl) -N, N, N ' , N' - tetramethyluronium hexafluorophosphate (304 mg, 0.800 mmol) was added and the solution was allowed to stir for 16 hours. The mixture was then purified by reverse phase preparative liquid chromatography to yield the pure product (2.9 mg, 0.0093 mmol, 1.6 %) ESI-MS m/z calc. 310.2, found 311.2 (M+l) + . Retention time of 3.40 minutes.
  • 2-Fluoro-nicotinic acid (84.7 mg, 0.-600 mmol, 3 -methyl- . butan-1-ol (52.9 mg, 0.600 mmol) and potassium bis (trimethylsilyl) amide (478 mg, 2.40 mmol) were combined in 0.6 mL of N, N-dimethylformamide and subjected to microwave irradiation for 3 minutes at 180 °C.
  • lH-Indazole-3 -carboxylic acid (32.4 mg, 0.200 mmol) and C- [1- (3, 4-Dimethoxy-phenyl) -cyclopentyl] -methylamine (47.1 g, 0.200 mmol) were dissolved in acetonitrile (1 mL) containing triethylamine (83.6 ⁇ L, 0.600 mmol).
  • Bath Solution #1 (in mM) NaCl 160, KCl 4.5, CaCl 2 2, MgCl 2 1, HEPES 10, pH 7.4 with NaOH.
  • Chloride-free bath solution Chloride salts in Bath Solution #1 are substituted with gluconate salts.
  • CC2-DMPE Prepared as a 10 mM stock solution in DMSO and stored at - 20°C.
  • DiSBAC 2 (3) Prepared as a 10 M stock in DMSO and stored at -20°C.
  • NIH3T3 mouse fibroblasts stably expressing ⁇ F508- CFTR are used for optical measurements of membrane potential.
  • the cells are maintained at 37 °C in 5% C0 2 and 90 % humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10 % fetal bovine serum, 1 X NEAA, ⁇ -ME, 1 X pen/strep, and 25 mM HEPES in 175 cm 2 culture flasks.
  • the cells were seeded at 30,000/well in 384- well matrigel -coated plates and cultured for 2 hrs at 37 °C before culturing at 27 °C for 24 hrs. for the potentiator assay.
  • the cells are cultured at 27 °C or 37 °C with and without compounds for 16 - 24 hours)
  • the FRT epithelia demonstrated resistances of 4 K ⁇ / cm 2 or more.
  • the solutions were maintained at 27 °C and bubbled with air.
  • the electrode offset potential and fluid resistance were corrected using a cell -free insert.
  • the current reflects the flow of Cl " through ⁇ F508-CFTR expressed in the apical membrane.
  • the I sc was digitally acquired using an MPIOOA-CE interface and AcqKJiowledge software (v3.2.6; BIOPAC Systems, Santa Barbara, CA) .
  • Typical protocol utilized a basolateral to apical membrane Cl " concentration gradient. To set up this gradient, normal ringer was used on the basolateral membrane, whereas apical NaCl was replaced by equimolar sodium gluconate
  • Typical protocol utilized a basolateral to apical membrane Cl " concentration gradient. To set up this gradient, normal ringers was used on the basolateral membrane and was permeabilized with nystatin (360 ⁇ g/ml), whereas apical NaCl was replaced by equimolar sodium gluconate (titrated to pH 7.4 with NaOH) to give a large Cl " concentration gradient across the epithelium. All experiments were performed 30 min after nystatin permeabilization. Forskolin (10 ⁇ M) and all test compounds were added to both sides of the cell culture inserts. The efficacy of the putative ⁇ F508-CFTR potentiators was compared to that of the known potentiator, genistein.
  • Basolateral solution in mM: NaCl (135), CaCl 2 (1.2), MgCl 2 (1.2), K 2 HP0 4 (2.4), KHP0 4 (0.6), N-2-hydroxyethylpiperazine-N' -2- ethanesulfonic acid (HEPES) (10) , and dextrose (10) .
  • the solution was titrated to pH 7.4 with NaOH.
  • Apical solution. in mM: Same as basolateral solution with NaCl replaced with Na Gluconate (135) .
  • FRT Fisher rat epithelial cells expressing ⁇ F508- CFTR (FRT ⁇ F508"CFTR ) were used for Ussing chamber experiments for the putative ⁇ F508-CFTR modulators identified from our optical assays.
  • the cells were cultured on Costar Snapwell cell culture inserts and cultured for five days at 37 °C and 5% C0 2 in Coon's modified Ham's F-12 medium supplemented with 5% fetal calf serum, 100 U/ml penicillin, and 100 ⁇ g/ml streptomycin.
  • the cells Prior to use for characterizing the potentiator activity of compounds, the cells were incubated at 27 °C for 16 - 48 hrs- to correct for the ⁇ F508-CFTR. To determine the activity of corrections compounds, the cells were incubated at 27 °C or 37 °C with and without the compounds for 24 hours.
  • the cells were incubated with 10 ⁇ M of the test compound for 24 hours at 37°C and the current density was compared to the 27°C and 37°C controls (% activity) . Prior to recording, the cells were washed 3X with extracellular recording medium to remove any remaining test compound. Preincubation with 10 ⁇ M of correction compounds significantly increased the cAMP- and genistein-dependent current compared to the 37°C controls.
  • Intracellular solution in mM Cs-aspartate (90) , CsCl (50), MgCl 2 (1), HEPES (10), and 240 ⁇ g/ml amphotericin-B (pH adjusted to 7.35 with CsOH) .
  • ⁇ IH3T3 mouse fibroblasts stably expressing ⁇ F508- CFTR are used for whole-cell recordings.
  • the cells are maintained at 37 °C in 5% C0 2 and 90 % humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10 % fetal bovine serum, 1 X NEAA, ⁇ -ME, 1 X pen/strep, and 25 mM HEPES in 175 cm 2 culture flasks.
  • the nonspecific phosphatase inhibitor F " (10 mM NaF) was added to the bath solution. Under these recording conditions, channel activity remained constant throughout the duration of the patch recording (up to 60 min) . Currents produced by positive charge moving from the intra- to extracellular solutions (anions moving in the opposite direction) are shown as positive currents.
  • the pipette potential (V p ) was maintained at 80 mV.
  • Extracellular solution (in mM) NMDG (150) , aspartic acid (150) , CaCl 2 (5) , MgCl 2 (2) , and HEPES (10) (pH adjusted to 7.35 with Tris base) .
  • Intracellular solution in mM
  • NMDG-C1 150
  • MgCl 2 (2) EGTA (5)
  • TES TES
  • Tris base 1
  • NIH3T3 mouse fibroblasts stably expressing ⁇ F508- CFTR are used for excised-membrane patch-clamp recordings.
  • the cells are maintained at 37 °C in 5% C0 2 and 90 % humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10 % fetal bovine serum, 1 X NEAA, ⁇ -ME, 1 X pen/strep, and 25 mM HEPES in 175 cm 2 culture flasks.
  • 2,500 - 5,000 cells were seeded on poly-L-lysine-coated glass coverslips and cultured for 24 - 48 hrs at 27 °C before use.
  • Compounds of the invention demonstrated activity as modulators of ATP binding cassette transporters, specifically CFTR.
  • the level of cAMP in FRT cells following 0.5 ⁇ M forskolin or test compound application was determined using a commercially available chemiluminiscent immunoassay system for mammalian cells called Tropix ® (Applied Biosystems, Bedford, MA) . Briefly, FRT cells were incubated for 15 minutes with a test compound in the presence and absence of 0.5 ⁇ M forskolin. The compounds were aspirated and the cells were then lysed and transferred along with the lysis buffer to a 96-well Tropix ® ELISA plate. A cAMP-Alk Phos conjugate is then added to the assay plate, followed by the addition of cAMP anti-body. After several wash and aspiration steps, Sapphire blue II solution is added and the fluorescence emission is read on the Topcount fluorescence reader, and the cAMP concentrations were determined using a cAMP standard curve that was present in each plate.
  • Tropix ® chemiluminiscent immunoassay system for mammalian cells
  • the example teaches that compounds can have potentiator activity without having an accompanying increase in cAMP concentrations.

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Abstract

L'invention porte sur des composés de formule (I), ou leurs sels pharmacocompatibles, modulateurs de l'activité des transporteurs ABC. Dans ladite formule: RB, n, B, RC, RD, RE, A, et Z sont décrit, répartis en classes et sous classes, dans la description. L'invention porte également sur des préparations pharmaceutiques, méthodes et trousses associés à la formule (I) utilisables comme modulateurs et pour le traitement de maladies et d'états pathologiques associés aux protéines transporteuses A, B et C.
EP04794652A 2003-10-08 2004-10-08 Modulateurs des transporteurs des cassettes de fixation de l'atp contenant des groupes cycloalkyle ou pyranyle Withdrawn EP1680411A2 (fr)

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Families Citing this family (93)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100074949A1 (en) 2008-08-13 2010-03-25 William Rowe Pharmaceutical composition and administration thereof
US8377952B2 (en) 2003-08-28 2013-02-19 Abbott Laboratories Solid pharmaceutical dosage formulation
US8025899B2 (en) 2003-08-28 2011-09-27 Abbott Laboratories Solid pharmaceutical dosage form
EP1664006A2 (fr) 2003-09-06 2006-06-07 Vertex Pharmaceuticals Incorporated Modulateurs de transporteurs a cassette de liaison a l'atp
MXPA06005343A (es) * 2003-11-14 2006-07-10 Vertex Pharma Tiazoles y oxazoles utiles como moduladores de transportadores con cassette de union a atp.
US7977322B2 (en) 2004-08-20 2011-07-12 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
FR2866886B1 (fr) * 2004-02-26 2007-08-31 Sanofi Synthelabo Derives d'aryl-et d'heteroaryl-akylcarbamates, leur preparation et leur application en therapeutique
WO2005087234A1 (fr) * 2004-03-05 2005-09-22 The Trustees Of The University Of Pennsylvania Traitement a faibles effets secondaires contre des affections liees a l'hyperlipidemie et l'hypercholesterolemie
FR2870846B1 (fr) 2004-05-25 2006-08-04 Sanofi Synthelabo Derives de tetrahydroisoquinolylsulfonamides, leur preparation et leur utilisation en therapeutique
EP2502913A3 (fr) * 2004-06-24 2013-11-27 Vertex Pharmaceuticals Incorporated Modulateurs de transporteurs de cassette de liaison a l´ATP
US8354427B2 (en) 2004-06-24 2013-01-15 Vertex Pharmaceutical Incorporated Modulators of ATP-binding cassette transporters
ES2656017T3 (es) 2004-06-24 2018-02-22 Vertex Pharmaceuticals Incorporated Moduladores de transportadores del casete de unión a ATP
EP1912983B1 (fr) 2005-08-11 2011-06-08 Vertex Pharmaceuticals, Inc. Modulateurs du regulateur de la conductance transmembranaire de la fibrose kystique
SI1945632T1 (sl) 2005-11-08 2014-03-31 Vertex Pharmaceuticals Incorporated Heterocikliäśni modulatorji za prenaĺ alce z atp-vezavno kaseto
AU2006331565A1 (en) * 2005-12-27 2007-07-05 Vertex Pharmaceuticals Incorporated Compounds useful in CFTR assays and methods therewith
US7671221B2 (en) * 2005-12-28 2010-03-02 Vertex Pharmaceuticals Incorporated Modulators of ATP-Binding Cassette transporters
PL1993360T3 (pl) 2005-12-28 2017-08-31 Vertex Pharmaceuticals Incorporated Stałe postacie n-[2,4-bis(1,1-dimetyloetylo)-5-hydroksyfenylo]-1,4- dihydro-4-oksochinolino-3-karboksyamidu
JP5165586B2 (ja) * 2005-12-28 2013-03-21 バーテックス ファーマシューティカルズ インコーポレイテッド 嚢胞性線維症の処置のためのＡＴＰ結合カセットトランスポーターのモジュレーターとしての、１−（ベンゾ［ｄ］［１，３］ジオキソール−５−イル）−Ｎ−（フェニル）シクロプロパン−カルボキサミド誘導体および関連化合物
ES2594156T3 (es) 2006-01-06 2016-12-16 Sunovion Pharmaceuticals Inc. Cicloalquilaminas como inhibidores de la recaptación de monoaminas
CN101437519A (zh) 2006-03-31 2009-05-20 艾博特公司 吲唑化合物
US7645789B2 (en) 2006-04-07 2010-01-12 Vertex Pharmaceuticals Incorporated Indole derivatives as CFTR modulators
US10022352B2 (en) 2006-04-07 2018-07-17 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
PT2674428T (pt) 2006-04-07 2016-07-14 Vertex Pharma Modeladores de transportadores de cassetes de ligação de atp
US8563573B2 (en) 2007-11-02 2013-10-22 Vertex Pharmaceuticals Incorporated Azaindole derivatives as CFTR modulators
AU2008248598B2 (en) 2007-05-07 2011-11-17 Novartis Ag Organic compounds
EP2164840A2 (fr) 2007-05-09 2010-03-24 Vertex Pharmaceuticals Incorporated Modulateurs de cftr
PT2178865E (pt) 2007-07-19 2015-11-16 Lundbeck & Co As H Amidas heterocíclicas com 5 membros e compostos relacionados
NZ583420A (en) 2007-08-24 2012-06-29 Vertex Pharma Isothiazolopyridinones useful for the treatment of (inter alia) cystic fibrosis
WO2009064959A1 (fr) 2007-11-16 2009-05-22 Vertex Pharmaceuticals Incorporated Modulateurs d'isoquinoléine de transporteurs de cassette de liaison à l'atp
UA95199C2 (en) * 2007-12-07 2011-07-11 Вертекс Фармасьютикалз Инкорпорейтед Aqueous formulation of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
EA201070700A1 (ru) 2007-12-07 2011-06-30 Вертекс Фармасьютикалз Инкорпорейтед Способы получения циклоалкилкарбоксамидопиридинбензойных кислот
US20100036130A1 (en) 2007-12-07 2010-02-11 Vertex Pharmaceuticals Incorporated Processes for producing cycloalkylcarboxamido-pyridine benzoic acids
MX2010006179A (es) 2007-12-07 2010-08-04 Vertex Pharma Formas solidas de acido 3-(6-(1-(2,2-difluorobenzo[d] [1,3]dioxol-5-il)ciclopropancarboxamido)-3-metilpiridin-2-il)benz oico.
CA2707857C (fr) 2007-12-10 2016-09-13 Novartis Ag Analogues d'amiloride spirocyclique
NZ720282A (en) 2008-02-28 2017-12-22 Vertex Pharma Heteroaryl derivatives as cftr modulators
ES2442945T3 (es) 2008-03-31 2014-02-14 Vertex Pharmaceuticals Inc. Derivados de piridilo como moduladores del CFTR
KR20110040818A (ko) 2008-06-10 2011-04-20 노파르티스 아게 상피 나트륨 채널 차단제로서의 피라진 유도체
EP2149554A1 (fr) 2008-07-30 2010-02-03 Bayer Schering Pharma Aktiengesellschaft Indolylamides en tant que modulateurs du récepteur EP2
EP2149552A1 (fr) 2008-07-30 2010-02-03 Bayer Schering Pharma AG Dérivés de benzamide 5,6 substitués en tant que modulateurs du récepteur EP2
EP2149551A1 (fr) 2008-07-30 2010-02-03 Bayer Schering Pharma AG Dérivés de N-(indol-3-ylalkyl)-(hétéro)arylamide en tant que modulateurs du récepteur EP2
JP2012504143A (ja) * 2008-09-29 2012-02-16 バーテックス ファーマシューティカルズ インコーポレイテッド ３−（６−（１−（２，２−ジフルオロベンゾ［ｄ］［１，３］ジオキソール−５−イル）シクロプロパンカルボキサミド）−３−メチルピリジン−２−イル）安息香酸の用量単位
MX2011004375A (es) * 2008-10-23 2013-03-07 Vertex Pharma Moduladores del regulador de conductancia transmembrana de fibrosis quistica.
TWI504395B (zh) 2009-03-10 2015-10-21 Substituted 3-amino-2-mercaptoquinoline as a KCNQ2 / 3 modifier
TW201038565A (en) 2009-03-12 2010-11-01 Gruenenthal Gmbh Substituted 2-mercapto-3-aminopyridines as KCNQ2/3 modulators
TWI475020B (zh) * 2009-03-12 2015-03-01 The substituted nicotine amide as a KCNQ2 / 3 modifier
TWI461197B (zh) 2009-03-12 2014-11-21 2-mercaptoquinoline-3-carboxamide as a KCNQ2 / 3 modifier
PL2408750T3 (pl) 2009-03-20 2016-02-29 Vertex Pharma Sposób otrzymywania modulatorów błonowego regulatora przewodnictwa swoistego dla mukowiscydozy
WO2010148191A2 (fr) * 2009-06-17 2010-12-23 Board Of Regents, The University Of Texas System Compositions et procédés pour des cyclofructanes en tant qu'agents de séparation
CA2776480A1 (fr) 2009-10-20 2011-04-28 Pfizer Inc. Nouveaux heteroaryl-imidazoles et heteroaryl-triazoles a titre de modulateurs de gamma-secretase
AU2010310449A1 (en) 2009-10-22 2012-05-03 Vertex Pharmaceuticals Incorporated Compositions for treatment of cystic fibrosis and other chronic diseases
BR112012024338B1 (pt) 2010-03-25 2021-09-28 Vertex Pharmaceuticals Incorporated Formas sólidas de (r)-1-(2,2-difluorbenzo[d] [1,3] dioxol-5-il)-n-(1-(2,3-diidroxipropil)-6-flúor-2- (1-hidróxi-2-metilpropan-2-il)-1h-indol-5-il)ciclopropanocarboxamida, composições farmacêuticas e dispersões sólidas compreendendo as mesmas, 5 processo de preparação e usos das mesmas, e kit compreendendo as mesmas
US8802868B2 (en) 2010-03-25 2014-08-12 Vertex Pharmaceuticals Incorporated Solid forms of (R)-1(2,2-difluorobenzo[D][1,3]dioxo1-5-yl)-N-(1-(2,3-dihydroxypropyl-6-fluoro-2-(1-hydroxy-2-methylpropan2-yl)-1H-Indol-5-yl)-Cyclopropanecarboxamide
EP2555755B2 (fr) 2010-04-07 2019-07-10 Vertex Pharmaceuticals Incorporated Compositions pharmaceutiques de l'acide 3-(6-(1-(2,2-difluorobenzo [d] [1,3] dioxol-5-yle) cyclopropane carboxamido)-3-méthylpyridin-2-yle) benzoïque et leur administration
AR081069A1 (es) 2010-04-07 2012-06-06 Vertex Pharma Formas solidas del acido 3-(6-(1-(2,2-difluorbenzo[d][1,3]dioxol-5-il)ciclopropancarboxamido)-3-metilpiridin-2-il)benzoico
EP3045452A1 (fr) 2010-04-22 2016-07-20 Vertex Pharmaceuticals Inc. Procédé de production de composés cycloalkyle-carboxamide-indole
US8563593B2 (en) 2010-06-08 2013-10-22 Vertex Pharmaceuticals Incorporated Formulations of (R)-1-(2,2-difluorobenzo[D] [1,3] dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide
AU2011293658B2 (en) 2010-08-23 2015-03-05 Vertex Pharmaceuticals Incorporated Pharmaceutical composition of (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxy propyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl) cyclopropanecarboxamide and administration thereof
PE20140214A1 (es) 2010-08-27 2014-02-19 Gruenenthal Chemie 2-oxo- y 2-tioxo-dihidroquinolina-3-carboxamidas sustituidos como moduladores kcnq2/3
AU2011295405B2 (en) 2010-08-27 2015-01-22 Grünenthal GmbH Substituted 2-oxy-quinoline-3-carboxamides as KCNQ2/3 modulators
CA2805932A1 (fr) 2010-08-27 2012-03-01 Gruenenthal Gmbh 2-aminoquinoleine-3-carboxamides substitues comme modulateurs de kcnq2/3
AU2011297937B2 (en) 2010-09-01 2015-10-01 Grunenthal Gmbh Substituted 1-oxo-dihydroisoquinoline-3-carboxamides as KCNQ2/3 modulators
US8372845B2 (en) 2010-09-17 2013-02-12 Novartis Ag Pyrazine derivatives as enac blockers
US8802700B2 (en) 2010-12-10 2014-08-12 Vertex Pharmaceuticals Incorporated Modulators of ATP-Binding Cassette transporters
ES2622154T3 (es) 2011-11-08 2017-07-05 Vertex Pharmaceuticals Incorporated Moduladores de transportadores de cassete de unión atp-binding
PL2806859T3 (pl) 2012-01-25 2019-11-29 Vertex Pharma Formulacje kwasu 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioksol-5- ilo)cyklopropanokarboksyamido)-3-metylopirydyn-2-ylo)benzoesowego
CA2865519C (fr) 2012-02-27 2018-01-02 Vertex Pharmaceuticals Incorporated Compositions pharmaceutiques renfermant une dispersion solide de n-[2,4-bis(1,1-dimethylethyl0-5-hydroxyphenyl-1]-1,4-dihydro-4-oxoquinolone-3-carboxamide destinees au traitement de la fibrose kystique
US8809340B2 (en) 2012-03-19 2014-08-19 Novartis Ag Crystalline form
US8674108B2 (en) 2012-04-20 2014-03-18 Vertex Pharmaceuticals Incorporated Solid forms of N-[2,4-bis(1,1-dimethylethy)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
CA2872012C (fr) 2012-05-08 2017-06-20 Aeromics, Llc Nouveaux procedes
WO2014014841A1 (fr) 2012-07-16 2014-01-23 Vertex Pharmaceuticals Incorporated Compositions pharmaceutiques de (r)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-n-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-méthylpropan-2-yl)-1h-indol-5-yl)cyclopropane- carboxamide et leur administration
WO2014031784A1 (fr) 2012-08-23 2014-02-27 Alios Biopharma, Inc. Composés pour le traitement d'infections virales par paramyxovirus
RS57831B2 (sr) 2012-11-02 2024-02-29 Vertex Pharma Farmaceutske kompozicije za lečenje bolesti posredovanih sa cftr
US20160151335A1 (en) * 2013-06-26 2016-06-02 Proteostasis Therapeutics, Inc. Methods of modulating cftr activity
BR112016003348B1 (pt) * 2013-08-21 2023-03-07 Alios Biopharma, Inc Compostos antivirais ou sais farmaceuticamente aceitáveis dos mesmos, composição farmacêutica e seus usos
SG11201604153UA (en) 2013-11-06 2016-07-28 Aeromics Inc Novel formulations
HUE054389T2 (hu) 2013-11-12 2021-09-28 Vertex Pharma Eljárás CFTR-mediálta betegségek kezelésére szolgáló gyógyászati kompozíciók elõállítására
WO2015138909A1 (fr) 2014-03-13 2015-09-17 Proteostasis Therapeutics, Inc. Composés, compositions et procédés pour augmenter l'activité du cftr
US9745292B2 (en) 2014-03-13 2017-08-29 Proteostasis Therapeutics, Inc. Compounds, compositions, and methods for increasing CFTR activity
SG11201607670XA (en) 2014-04-15 2016-10-28 Vertex Pharma Pharmaceutical compositions for the treatment of cystic fibrosis transmembrane conductance regulator mediated diseases
CA2952862A1 (fr) 2014-06-19 2015-12-23 Proteostasis Therapeutics, Inc. Composes, compositions et procedes pour augmenter l'activite du cftr
EP3203840B1 (fr) 2014-10-06 2020-08-05 Vertex Pharmaceuticals Incorporated Modulateurs du régulateur de conductance transmembranaire de la mucoviscidose
EP3204358B1 (fr) 2014-10-07 2018-09-19 Vertex Pharmaceuticals Incorporated Co-cristaux de modulateurs du régulateur de conductance transmembranaire de la mucoviscidose
CA2966023A1 (fr) 2014-10-31 2016-05-06 Abbvie S.A.R.L. Tetrahydropyrannes substitues et methode d'utilisation associee
HUE055423T2 (hu) 2014-11-18 2021-11-29 Vertex Pharma Eljárás nagy áteresztõképességû tesztelõ nagy teljesítményû folyadék-kromatográfia elvégzésére
WO2016105477A1 (fr) 2014-12-23 2016-06-30 Proteostasis Therapeutics, Inc Dérivés d'amides 5-phényl- ou 5-hétéroarylthiazol-2-carboxyliques servant au traitement, entre autres, de la fibrose cystique
MA41253A (fr) 2014-12-23 2017-10-31 Proteostasis Therapeutics Inc Composés, compositions et procédés pour augmenter l'activité du cftr
US10344023B2 (en) 2014-12-23 2019-07-09 Proteostasis Therapeutics, Inc. Derivatives of 3-heteroarylisoxazol-5-carboxylic amide useful for the treatment of inter alia cystic fibrosis
US10738011B2 (en) 2014-12-23 2020-08-11 Proteostasis Therapeutics, Inc. Derivatives of 5-(hetero)arylpyrazol-3-carboxylic amide or 1-(hetero)aryltriazol-4-carboxylic amide useful for the treatment of inter alia cystic fibrosis
WO2017019589A1 (fr) 2015-07-24 2017-02-02 Proteostasis Therapeutics, Inc. Composés, compositions et procédés pour augmenter l'activité du cftr
NZ741093A (en) 2015-10-06 2022-12-23 Proteostasis Therapeutics Inc Compounds, compositions, and methods for modulating cftr
US10662207B2 (en) 2016-04-07 2020-05-26 Proteostasis Therapeutics, Inc. Compounds, compositions, and methods for modulating CFTR
ES2954658T3 (es) 2016-06-21 2023-11-23 Proteostasis Therapeutics Inc Compuestos, composiciones y procedimientos para aumentar la actividad de CFTR
EP4017849A1 (fr) * 2019-08-21 2022-06-29 Kalvista Pharmaceuticals Limited Inhibiteurs d'enzyme

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2846438A (en) * 1954-03-15 1958-08-05 Olin Mathieson Nu-(beta-diethylaminoethyl) isonicotinamide
GB874206A (en) * 1956-09-05 1961-08-02 Knoll Ag Basic derivatives of salicylamide
FR2665440B1 (fr) * 1990-07-31 1994-02-04 Lipha Nouveaux cycloalkylsulfonamides substitues, procedes de preparation et medicaments les contenant.
US5281714A (en) * 1990-08-16 1994-01-25 American Home Products Corporation N,N',N'-trisubstituted-5-bisaminomethylene-1,3-dioxane-4,6-dione inhibitors of acyl-CoA: cholesterol-acyl transferase
US6632836B1 (en) * 1998-10-30 2003-10-14 Merck & Co., Inc. Carbocyclic potassium channel inhibitors
FR2796070B1 (fr) * 1999-07-06 2003-02-21 Lipha Derives de benzodiazepines utilisables dans le traitement de dyslipidemies, de l'atherosclerose et du diabete, compositions pharmaceutiques les contenant et procedes de preparation
AUPQ309399A0 (en) * 1999-09-28 1999-10-21 Fujisawa Pharmaceutical Co., Ltd. Benzothiazoline derivatives
EP1244617B1 (fr) * 1999-12-27 2005-02-16 Ortho-McNeil Pharmaceutical, Inc. Derives d'aminoalkylamide substitues utilises en tant qu'antagonistes de l'hormone folliculostimulante
US6451814B1 (en) * 2000-07-17 2002-09-17 Wyeth Heterocyclic β-3 adrenergic receptor agonists
US6908934B2 (en) * 2001-06-11 2005-06-21 Merck & Co., Inc. Therapeutic compounds for treating dyslipidemic conditions
PA8557501A1 (es) * 2001-11-12 2003-06-30 Pfizer Prod Inc Benzamida, heteroarilamida y amidas inversas
AU2002366362A1 (en) * 2001-12-18 2003-06-30 Bayer Aktiengesellschaft 2-substituted pyrrolo(2.1-a)isoquinolines against cancer
JP4709488B2 (ja) 2002-01-18 2011-06-22 メルク・シャープ・エンド・ドーム・コーポレイション Ｅｄｇ受容体作動薬としてのＮ−（ベンジル）アミノアルキルカルボン酸化合物、ホスフィン酸化合物、ホスホン酸化合物およびテトラゾール類
TW200307539A (en) * 2002-02-01 2003-12-16 Bristol Myers Squibb Co Cycloalkyl inhibitors of potassium channel function

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2005035514A2 *

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WO2005035514A2 (fr) 2005-04-21
MXPA06004005A (es) 2006-06-28
US20120035179A1 (en) 2012-02-09
AU2004279855A1 (en) 2005-04-21
US7598412B2 (en) 2009-10-06
KR20060121909A (ko) 2006-11-29
US20100125090A1 (en) 2010-05-20
WO2005035514A3 (fr) 2005-07-14
RU2006115602A (ru) 2007-11-20
ZA200603515B (en) 2007-11-28
CA2540978A1 (fr) 2005-04-21
JP2007509044A (ja) 2007-04-12
US20050148648A1 (en) 2005-07-07
NZ546365A (en) 2010-01-29
CN1886393A (zh) 2006-12-27
IL174820A0 (en) 2006-08-20
NO20062040L (no) 2006-06-06

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